This project is designed to study the relationship between sickling and the oxygen transport of blood. Sickling is a function of blood oxygen saturation and is therefore affected by factors which modify oxygenation. The overall objective is to define the extent of organ involvement and some parameters of blood oxygen transport (pulmonary functions, response to exercise, blood oxygen affinity, and sickling) in a small number of patients with sickle cell anemia. The effects of agents which modify one or more of the known properties of blood oxygenation or sickling can then be investigated. The current protocol is designed to test the effect of low dose carbon monoxide on sickling and exercise tolerance. In addition, in vitro studies are directed toward an understanding of the molecular and cellular mechanisms which regulate oxygenation and gellation of hemoglobin within sickled cells. We plan to continue the Clinical Protocol and study the effect of the alteration of blood oxygen affinity on sickling, by the administration of carbon monoxide in low doses to selected patients. We plan to investigate the mechanism of the low oxygen affinity of ISC's and to attempt to understand whether these unique cells are harmful or beneficial in sickle cell anemia patients. A model of the respiratory function of normal blood will be built up and applied to the problem of sickle cell anemia. To this end, the kinetic and equilibrium oxygenation properties of sickle blood will be carefully studied.